Since the initial creation of dendrimers in the early 1980s, these precise, core-shell nano-constructs have become widely accepted as perhaps the most important members of the recently recognized fourth major architectural class of macromolecules known as dendritic polymers. [For example, see Dendrimers and Other Dendritic Polymers, eds. Jean J. Fréchet and Donald A. Tomalia, pub. John Wiley & Sons, Ltd. (2001), pp. 14-15; D. A. Tomalia, et al., Polym. J. (Tokyo), 17, 117-32 (1985); and D. A. Tomalia, Prog. Polym. Sci., 30, 294-324 (2005).] Particular interest is focused on the sub-class, dendrimers, in that they represent a broad range of organic/organo-metallic compositions and architectures that may be structurally controlled as a function of (a) size, (b) shape, (c) flexibility and (d) surface chemistry in the nanoscale region [see D. A. Tomalia, et al., Angew. Chem., 102(2), 119-57, (1990); and Angew. Chem. Int. Ed. Engl., 29(2), 138-75, (1990)]. It is from this perspective that dendrimers are viewed as fundamental, nanometer-sized building blocks [see D. A. Tomalia, Advanced Materials, 6(7/8), 529 (1994); and “Dendrimers—An Enabling Synthetic Science to Controlled Organic Nanostructures,” D. Tomalia, R. Esfand, K. Mardel, S. A. Henderson, G. Holan, Chapter 20 in Handbook of Nanoscience, Engineering and Technology (W. A. Goddard III, D. W. Brenner, S. E. Lyshevski, G. J. Irafrate, eds.) CRC Press, Boca Raton, 20.1-20.34 (2002); and D. A. Tomalia, Prog. Polym. Sci., 30, 294-324 (2005)] that enable the construction of a wide range of nanoscale complexity/devices exhibiting important uses and properties in many fields including but not limited to the biomedical [discussed in “Dendrimers—An Enabling Synthetic Science to Controlled Organic Nanostructures,” D. Tomalia, R. Esfand, K. Mardel, S. A. Henderson, G. Holan, Chapter 20 in Handbook of Nanoscience, Engineering and Technology (W. A. Goddard III, D. W. Brenner, S. E. Lyshevski, G. J. Irafrate, eds.) CRC Press, Boca Raton, 20.1-20.34 (2002); and R. Esfand, et al., Drug Discovery Today, 8(6), 427-436 (2001); and Dendrimers and Other Dendritic Polymers, eds. Jean J. Fréchet and Donald A. Tomalia, pub, John Wiley & Sons, Ltd. (2001)], nano-electronics, advanced materials [for example in D. A. Tomalia, Advanced Materials, 6(718), 529 (1994); and R. Esfand, et al., Drug Discovery Today, 8(6), 427-436 (2001)], and nano-catalyst fields Dendrimers and Other Dendritic Polymers, eds. Jean J. Fréchet and Donald A. Tomalia, pub. John Wiley & Sons, Ltd. (2001); “Dendrimers—An Enabling Synthetic Science to Controlled Organic Nanostructures,” D. Tomalia, R. Esfand, K. Mardel, S. A. Henderson, G. Holan, Chapter 20 in Handbook of Nanoscience, Engineering and Technology (W. A. Goddard III, D. W. Brenner, S. E. Lyshevski, G. J. Irafrate, eds.) CRC Press, Boca Raton, 20.1-20.34 (2002); G. R. Newkome, et al., Dendritic Molecules; VCH: Weinheim, 1996; and F. Zeng, et al., Chem. Rev. 97, 1681-1712 (1997)].
Covalent construction of dendrimers by the assembly of reactive monomers [see for example D. A. Tomalia, Scientific American, 272(5), 62-6 (1995)], branch cells [see Dendrimers and Other Dendritic Polymers, eds. Jean J. Fréchet and Donald A. Tomalia, pub. John Wiley & Sons, Ltd. (2001); “Dendrimers—An Enabling Synthetic Science to Controlled Organic Nanostructures,” D. Tomalia, R. Esfand, K. Mardel, S. A. Henderson, G. Holan, Chapter 20 in Handbook of Nanoscience, Engineering and Technology (W. A. Goddard III, D. W. Brenner, S. E. Lyshevski, G. J. Irafrate, eds.) CRC Press, Boca Raton, 20.1-20.34 (2002); and M. K. Lothian-Tomalia, et al., Tetrahedron, 3(45), 15495-15513 (1997)], or dendrons [see for example M. K. Lothian-Tomalia, et al., Tetrahedron, 53(45), 15495-15513 (1997); and O. A. Matthews, et al., Prog. Polym. Sci., 23, 1-56, 1998] around atomic or molecular cores with adherence to either divergent or convergent dendritic branching principles is now well documented [see for example D. A. Tomalia, et al., Polym. J. (Tokyo), 17, 117-32 (1985); and G. R. Newkome, C. N. Moorfield, F. Vögtle, Dendritic Molecules; VCH: Weinheim, 1996] and known to those skilled in this art. [See the general discussions in Dendrimers and Other Dendritic Polymers, eds. Jean J. Fréchet and Donald A. Tomalia, pub. John Wiley & Sons, Ltd. (2001), pp. 20-23.]
Convergent synthesis can provide the joining of differentiated dendrons as shown by J. M. J. Fréchet in J. Org. Chem., 69, 46-53 (2004). Such a systematic occupation of nano-space around cores with monomers or branch cells, as a function of generational growth stages (i.e., monomer shells), to give discrete, quantized bundles of mass has been well demonstrated [for example D. A. Tomalia, Materials Today, pp. 34-46, March 2005; and G. J. Kallos, et al., Rapid Commun. Mass Spectrom., 5(9), 383-6 (1991)]. A general scheme for the synthesis of cystamine core: poly(amidoamine) dendrimers (e.g., PAMAM dendrimers) is illustrated in Scheme 1 below.

This Scheme shows divergent synthesis of cystamine-dendri-PAMAM dendrimers utilizing the iterative sequence: (a) alkylation with methyl acrylate, followed by (b) amidation with excess ethylenediamine to produce G=3-7 PAMAM dendrimers possessing disulfide linkage in their cores. [See for example U.S. Pat. No. 6,020,457.]
These parameters have been shown to be mathematically predictable [see for example M. K. Lothian-Tomalia, et al., Tetrahedron, 53(45), 15495-15513 (1997); D. A. Tomalia, Aldrichimica Acta, 26(4), 91-101 (1993); and D. A. Tomalia, Advanced Materials, 6(7/8), 529 (1994)] (see FIG. 2) and are confirmed by mass spectrometry [see G. J. Kallos, et al., Rapid Commun. Mass Spectrom., 5(9), 383-6 (1991); P. R. Dvornic and D. A. Tomalia, Macromol. Symp., 98 (35th IUPAC International Symposium on Macromolecules, 1994) 403-28 (1995); D. A. Tomalia, H. D. Durst; Topics in Current Chemistry Vol. 165: Supramolecular Chemistry I—Directed Synthesis and Molecular Recognition; 193-313; E. Weber (editor), Springer-Verlag Berlin Heidelberg (1993); and C. Hummelen, et al. Chem. Eur. J, 3, 1489-1493. (1997)], gel electrophoresis [see H. M. Brothers II, et al., J. of Chromatography A, 814, 233-246 (1998); and C. Zhang, D. A. Tomalia, Chapter 10 in Dendrimers and Other Dendritic Polymers, eds. Jean J. Fréchet and Donald A. Tomalia, pub. John Wiley & Sons, Ltd. (2001),] and other analytical methods [see H. M. Brothers II, et al., J. of Chromatography A, 814, 233-246 (1998); C. Zhang, D. A. Tomalia, Chapter 10 in Dendrimers and Other Dendritic Polymers, eds. Jean J. Fréchet and Donald A. Tomalia, pub. John Wiley & Sons, Ltd. (2001); and P. L. Dubin, et al., J. Chromatogr., 635(1), 51-60 (1993)]. At present over 100 different compositional dendrimer families with over 1000 different surface modifications have been reported [see D. A. Tomalia, Materials Today, pp. 34-46, March 2005].
Access to this level of macromolecular structure control has created substantial interest in the use of dendrimer structures as unimolecular mimics of globular proteins [see for example R. Esfand, D. A. Tomalia, Drug Discovery Today, (6) 8, 427-436 (2001); S. Hecht, J. M. J. Fréchet, Angew. Chem. Int. Ed., 40(1), 74-91 (2001); and D. A. Tomalia, et al., Proc. Nat. Acad. Of Sciences, 29(8), 5081-5087 (2002)], micelles [see D. A. Tomalia, Macromol. Symp., 101, 243-255 (1996); N. J. Turro, W. Chen, M. F. Ottaviani, In Dendrimers and Other Dendritic Polymers; Fréchet, J. M. J., Tomalia, D. A., Eds.; John Wiley & Sons: West Sussex, pp 309-330 (2001); and D. Watkins, et al., Langmuir, 13, 3136-3141 (1997)] and a variety of other biological self-assemblies [for example D. A. Tomalia, et al., Angew. Chem. Int. Ed. Engl., 29(2), 138-75, (1990); and J. F. Kukowska-Latallo, et al., Proc. Natl. Acad. Sci., 93, 4897-4902, May (1996)].
Using strictly abiotic methods, it has been widely demonstrated over the past decade that dendrimers can be routinely constructed with control that rivals the structural regulation found in biological systems. Such mimicry and comparison of spherical dendrimers to proteins was made as early as 1990. [For example D. A. Tomalia, et al., Angew. Chem., 102(2), 119-57, (1990); Angew. Chem. Int. Ed. Engl., 29(2), 138-75, (1990).] The close scaling of size [see R. Esfand, D. A. Tomalia, Drug Discovery Today, (6) 8, 427-436 (2001)], shape [see D. A. Tomalia, et al., Proc. Nat. Acad. Of Sciences, 29(8), 5081-5087 (2002); and D. A. Tomalia, et al., Tetrahedron, 59, 3799-3813 (2003)] and quasi-equivalency comparison of dendrimer surfaces [see V. Percec, et al., J. Am. Chem. Soc., 118, 9855-9866 (1996); V. Percec, et al., Nature, 391, 161-164 (1998); and S. D. Hudson, et al., Science, 278, 449-452 (1997)] to nanoscale biostructures is both striking and provocative (See FIG. 3).